Project Summary/Abstract Small cell lung cancer (SCLC) is a high-grade neuroendocrine cancer with no effective targeted therapies. Identifying therapeutic targets in SCLC has been challenging, partly because driver mutations in SCLC are primarily loss of function, involving the tumor suppressor genes RB1 and TP53. While TP53 is highly mutated in many adult solid tumors, the near-universal loss of RB1 (protein pRB) is unique to SCLC. I propose to identify new therapeutic targets in SCLC by investigating epistatic and synthetic lethal interactions with pRB loss, with the former being targets acting downstream of pRB and the latter representing dependencies created specifically by pRB loss. I have employed both of these strategies to identify two novel targets, KDM5A and AURKB, that are required for SCLC proliferation and whose specific function is to regulate neuroendocrine differentiation and chromosomal segregation, respectively. In Aim 1, I will use biochemical and genetic approaches to determine the specific mechanism by which KDM5A regulates ASCL1, a pulmonary neuroendocrine lineage transcriptional activator that is required for SCLC tumor formation. In Aim 2, based on my preliminary data from a CRISPR screen, I hypothesize that other regulators of chromosomal segregation are synthetic lethal with RB1 loss. I will use direct fluorescence-based competition assays to validate true synthetic lethal interactions. I will then use time-lapse microscopy to determine the underlying mechanism by which pRB loss exacerbates the mitotic phenotype caused by loss of other chromosomal segregation genes. In Aim 3, I will ask whether KDM5A is necessary for tumor initiation and/or tumor maintenance in vivo using a novel CRISPR-based genetically-engineered mouse model of SCLC that I developed. I'm a medical oncologist with a research background in cancer biology applying for a K08 award with a long-term goal of becoming a tenure-track independent laboratory investigator. I envision developing an independent research program investigating the mechanisms responsible for SCLC pathogenesis with the ultimate goal of identifying new therapies for SCLC patients. During my proposed K08 research training, I will perform mentored research in the laboratory of Dr. William Kaelin at the Dana-Farber Cancer Institute (DFCI). I plan to spend 90% of my time on research and 10% on patient care seeing thoracic oncology patients. I have organized an outstanding advisory committee to help guide my research and career development with faculty members at DFCI, Harvard Medical School, and MIT that are experts in specific areas of my proposed research including: Dr. Stuart Orkin, Dr. David Pellman, Dr. Tyler Jacks, and Dr. Stephen Blacklow. Dr. Bruce Johnson, a world-renowned lung cancer clinical trialist, will serve as my clinical advisor. This outstanding environment at DFCI supplemented with coursework and conferences will help me achieve my long-term career aspirations.